Proceedings of the Symposium ‘Angiotensin AT1 Receptors: From Molecular Physiology to Therapeutics’: FUNCTIONS OF ANGIOTENSIN PEPTIDES IN THE ROSTRAL VENTROLATERAL MEDULLA

• 1 It was first shown several years ago that the rostral part of the ventrolateral medulla (VLM) contains a high density of receptor binding sites for angiotensin II (AngII). In the present paper we briefly review recent studies aimed at determining the actions of both exogenous and endogenous angiotensin peptides in the rostral VLM, as well as their specific sites of action.
• 2 The results of these studies have shown that angiotensin peptides can excite pressor and sympathoexcitatory neurons in the rostral VLM, but do not appear to affect non-cardiovascular neurons in this region.
• 3 It is known that pressor neurons in the rostral VLM include both catecholamine and non-catecholamine neurons. There is evidence that, at least in conscious rabbits, both of these types of neurons are activated by AngII. The specific endogenous angiotensin peptide or peptides that affect pressor neurons in the rostral VLM have not yet been definitively identified.
• 4 It is also possible that different angiotensin peptides may have different effects on pressor neurons in the rostral VLM, mediated by different receptors. Further studies will be needed to define these different functions as well as the specific receptors and cellular mechanisms that subserve them.

     

家兔延髓吻端腹外侧区在“人中”穴加压效应中的作用

延髓吻端腹外测区(Rostral ventrolateral medulla,RVL)微量注射红藻氨酸(Kainic acid,KA)前,分别用弱、强电刺激“人中”穴时可引起动脉血压(BP)显著升高,心率(HR)明显增快。一侧或双侧RVL注射KA后,再用弱、强电刺激“人中”穴时,BP、HR的反应基本消失。结果表明,RVL在“人中”穴加压效应中起关键性作用。     

CVLM咪唑啉-I和α_2-肾上腺素受体共同参与可乐定的降压效应

目的　探讨大鼠尾端延髓腹外侧区 (CVLM)咪唑啉 I受体 (I1R)和α2 肾上腺素受体 (α2 AR)在介导可乐定中枢降压机制中的作用。方法　在氨基甲酸乙酯麻醉SD大鼠中 ,观察CVLM内局部给予I1R和α2 AR阻断剂后对基础血压(BP)、心率 (HR)以及外周给予可乐定导致降压效应的变化。结果　双侧CVLM分别微量注射选择性α2 AR阻断剂育亨宾 (单侧剂量 5 0 0 pmol·L-1,10 0nl,n =8)或I1R和α2 AR混合性阻断剂idazoxan(单侧剂量 2nmol·L-1,10 0nl,n =10 )后不仅明显降低BP和HR(P <0 0 1) ,而且能明显减弱静脉给予可乐定 (5 μg·kg-1)导致的降压效应 (P <0 0 1) ,此外 ,idazoxan对可乐定降压效应的减弱作用高于育亨宾 (P <0 0 1)。结论　CVLM内I1R和α2 AR共同参与维持紧张性心血管活动和介导可乐定的降压效应     

Sex differences in circadian timing systems: Implications for disease

Virtually every eukaryotic cell has an endogenous circadian clock and a biological sex. These cell-based clocks have been conceptualized as oscillators whose phase can be reset by internal signals such as hormones, and external cues such as light. The present review highlights the inter-relationship between circadian clocks and sex differences. In mammals, the suprachiasmatic nucleus (SCN) serves as a master clock synchronizing the phase of clocks throughout the body. Gonadal steroid receptors are expressed in almost every site that receives direct SCN input. Here we review sex differences in the circadian timing system in the hypothalamic–pituitary–gonadal axis (HPG), the hypothalamic–adrenal–pituitary (HPA) axis, and sleep–arousal systems. We also point to ways in which disruption of circadian rhythms within these systems differs in the sexes and is associated with dysfunction and disease. Understanding sex differentiated circadian timing systems can lead to improved treatment strategies for these conditions.     

Adenosine A2A receptors in ventral striatum, hypothalamus and nociceptive circuitry implications for drug addiction, sleep and pain

Adenosine A2A receptors localized in the dorsal striatum are considered as a new target for the development of antiparkinsonian drugs. Co-administration of A2A receptor antagonists has shown a significant improvement of the effects of l-DOPA. The present review emphasizes the possible application of A2A receptor antagonists in pathological conditions other than parkinsonism, including drug addiction, sleep disorders and pain. In addition to the dorsal striatum, the ventral striatum (nucleus accumbens) contains a high density of A2A receptors, which presynaptically and postsynaptically regulate glutamatergic transmission in the cortical glutamatergic projections to the nucleus accumbens. It is currently believed that molecular adaptations of the cortico-accumbens glutamatergic synapses are involved in compulsive drug seeking and relapse. Here we review recent experimental evidence suggesting that A2A antagonists could become new therapeutic agents for drug addiction. Morphological and functional studies have identified lower levels of A2A receptors in brain areas other than the striatum, such as the ventrolateral preoptic area of the hypothalamus, where adenosine plays an important role in sleep regulation. Although initially believed to be mostly dependent on A1 receptors, here we review recent studies that demonstrate that the somnogenic effects of adenosine are largely mediated by hypothalamic A2A receptors. A2A)receptor antagonists could therefore be considered as a possible treatment for narcolepsy and other sleep-related disorders. Finally, nociception is another adenosine-regulated neural function previously thought to mostly involve A1 receptors. Although there is some conflicting literature on the effects of agonists and antagonists, which may partly be due to the lack of selectivity of available drugs, the studies in A2A receptor knockout mice suggest that A2A receptor antagonists might have some therapeutic potential in pain states, in particular where high intensity stimuli are prevalent.     

Modulators in concert for cognition: modulator interactions in the prefrontal cortex

Research on the regulation and function of ascending noradrenergic, dopaminergic, serotonergic, and cholinergic systems has focused on the organization and function of individual systems. In contrast, evidence describing co-activation and interactions between multiple neuromodulatory systems has remained scarce. However, commonalities in the anatomical organization of these systems and overlapping evidence concerning the post-synaptic effects of neuromodulators strongly suggest that these systems are recruited in concert; they influence each other and simultaneously modulate their target circuits. Therefore, evidence on the regulatory and functional interactions between these systems is considered essential for revealing the role of neuromodulators. This postulate extends to contemporary neurobiological hypotheses of major neuropsychiatric disorders. These hypotheses have focused largely on aberrations in the integrity or regulation of individual ascending modulatory systems, with little regard for the likely possibility that dysregulation in multiple ascending neuromodulatory systems and their interactions contribute essentially to the symptoms of these disorders. This review will paradigmatically focus on neuromodulator interactions in the PFC and be further constrained by an additional focus on their role in cognitive functions. Recent evidence indicates that individual neuromodulators, in addition to their general state-setting or gating functions, encode specific cognitive operations, further substantiating the importance of research concerning the parallel recruitment of neuromodulator systems and interactions between these systems.     

Ventrolateral hypothalamic lesions in obese-hyperglycemic mice (obob)

Summary Bilateral electrolytic lesions were induced on the ventrolateral nucleus (VLN) of obese-hyperglycemic mice (obob) and lean littermates, with or without previous body weight reduction. All lean animals with VLN damage died within the first four post-operative days. In contrast, all obese mice (obob) with no prior body weight reduction recovered following an initial period of aphagia and rapid body weight loss. Three out of five reducedobob mice died following VLN lesions. - Two months after the operation the body weight of all lesionedobob mice stabilized at a level significantly lower than that of the sham operated obese; their serum immunoreactive insulin and blood glucose levels were also lower. - These data indicate thatobob mice respond normally to bilateral lesions of VLN and that their excess adiposity, by protecting them during the early post-operative period, facilitates their recovery. The final stabilization of the body weight of lesionedobob at a level lower than that of control mice is compatible with the view that the VLN acts as the low set point controller in the regulation of body weight.

---

Ventrolaterale hypothalamische Läsionen bei obes- hyperglykämischen Mäusen (obob)

Zusammenfassung Bilaterale electrolytische Läsionen wurden in den ventrolateralen Kernen (VLN) von obeshyperglykämischen Mäusen (obob) und normalen Wurfgeschwistern mit oder ohne vorherige Gewichtsreduktion vorgenommen. Alle normalen Mäuse mit VLN-Läsionen starben innerhalb von vier Tagen nach der hypothalamischen Operation. Im Gegensatz dazu erholten sich alle fetten Mäuse (obob), deren Gewicht vor der hypothalamischen Operation nicht reduziert worden war, nach einer Periode von Aphagie und rapidem Gewichtsverlust. Drei von fünf gewichtsreduziertenobob-Mäusen starben nach der VLN-Operation. - Zwei Monate nach der Operation stabilisierten sich die Gewichte aller operiertenobob-Tiere auf einem statistisch signifikant niedrigeren Niveau, als dem der scheinoperierten fetten Mäuse entsprach. Immunoreaktives Insulin und Blutglucose waren bei diesen Tieren ebenfalls erniedrigt. - Die Ergebnisse deuten darauf hin, daßobob-Mäuse eine normale Reaktion auf die bilaterale Zerstörung der VLN zeigen und daß die überschüssige Fettmasse zu ihrer Erholung beitrug, indem sie ihnen in der Zeit unmittelbar nach der Operation Schutz gewährte. Die spätere Gewichtsstabilisation derobob auf einem subnormalen Niveau ist mit der gegenwärtigen Ansicht zu vereinbaren, daß die ventrolateralen hypothalamischen Kerne als die Regulatoren der unteren Körpergewichtsgrenze dienen.

---

Lésions ventrolatérales de l'hypothalamus chez des souris obèses hyperglycémiques (obob)

Résumé Des lésions électrolytiques bilatérales du noyau ventrolateral (VLN) ont été pratiquées chez des souris obèses-hyperglycémiques (obob) et chez des souris de même portée non-obèses, avec ou sans réduction pondérale préalable. Tous les animaux maigres porteurs de lésions VLN décédèrent dans les quatre premiers jours post opératoires. Au contraire, toutes les souris obèses (obob) sans réduction pondérale préalable récupérèrent après une courte période d'aphagie et de perte de poids. Trois des cinq sourisobob préalablement soumises à un régime amaigrissant succombèrent après lésion du VLN. Deux mois après l'opération, le poids de tous lesobob porteurs de lésions du VLN atteignit un niveau stable mais significativement inférieur à celui des animaux soumis à une opération simulée. Il en fut de même du taux d'insuline immunoréactive et du glucose sanguin. -Ces résultats indiquent que la réponse desobob aux lésions bilatérales du VLN est normale et que leur excès de tissu adipeux les protège dans la période post opératoire et facilite leur récupération. La stabilisation du poids desobob à un niveau inférieur à la normale est compatible avec l'hypothèse que le VLN contrôle la limite inférieure du poids.